EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype

Margherita Ciano; Giada Mantellato; Martin Connolly; Mark Paul-Clark; Saffron Willis-Owen; Miriam F Moffatt; William O C M Cookson; Jane A Mitchell; Michael I Polkey; Simon M Hughes; Paul R Kemp; S Amanda Natanek

doi:10.1038/s41598-019-45567-4

EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype

Margherita Ciano, Giada Mantellato, Martin Connolly, Mark Paul-Clark, Saffron Willis-Owen, Miriam F Moffatt, William O C M Cookson, Jane A Mitchell, Michael I Polkey, Simon M Hughes, Paul R Kemp, S Amanda Natanek

Nutrition and Dietetic Research Group, Division of Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK; Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.
Population Health and Occupational Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
RBHT Royal Brompton & Harefield NHS Foundation Trust
1] Randall Division of Cell and Molecular Biophysics, King's College London, London, UK. [2] Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
Imperial College London

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Abstract

A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.

Original language	English
Article number	9218
Pages (from-to)	9218
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-45567-4
Publication status	Published - 25 Jun 2019

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EGF receptor (EGFR) inhibition_CIANO_Accepted10April2019_GOLD VoRFinal published version, 2.39 MBLicence: CC BY

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Ciano, M., Mantellato, G., Connolly, M., Paul-Clark, M., Willis-Owen, S., Moffatt, M. F., Cookson, W. O. C. M., Mitchell, J. A., Polkey, M. I., Hughes, S. M., Kemp, P. R., & Natanek, S. A. (2019). EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype. Scientific Reports, 9(1), 9218. Article 9218. https://doi.org/10.1038/s41598-019-45567-4

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abstract = "A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.",

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AU - Willis-Owen, Saffron

AU - Moffatt, Miriam F

AU - Cookson, William O C M

AU - Mitchell, Jane A

AU - Polkey, Michael I

AU - Hughes, Simon M

AU - Kemp, Paul R

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EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype

Abstract

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